Project Summary/Abstract Rapid development of new target drugs, essential to the improvement of public health, is reliant on the ability to efficiently synthesize a wide range of organic molecules, commonly substituted arenes. Regioselective derivatization of aromatic substrates is most commonly accomplished using cross-coupling reactions. Unfortunately, regioselectivity is attained at the expense of stoichiometric quantities of various, often toxic, waste products. To decrease the need for costly separation associated with current synthetic practices, direct functionalization of C-H bonds provides a promising, atom-economical alternative. However, controlling reaction selectivity becomes challenging due to the large number of energetically similar C-H bonds in any given arene substrate. While ?directed activation? strategies are now well-known to provide selective ortho-functionalization of substituted arenes, analogous one-step directed functionalization of arenes at meta- and para- C-H bonds has remained elusive. In this project, catalysts will be developed which allow for direct, one-step, meta- and para- C-H functionalization of benzaldehydes and benzylamines. Developed systems will rely on ligand ?tethers? which will dock and orient the substrate molecule in such a way that kinetically favors reaction at the desired C-H bond. In principle, the methodology developed could be used to selectively functionalize ANY C-H bond in ANY molecule that contains an aldehyde or amine functional group. This extremely powerful contribution to the field of synthetic organic chemistry has the potential to revolutionize pharmaceutical synthesis. Three specific aims have been developed to further guide the proposed work. (1) Design and synthesis of tether ligands. Designed ligands must serve to both dock and orient the substrate in the proper manner for regioselective functionalization. Ligands will be designed computationally to ensure that the geometrical parameters for proper orientation are met. (2) Synthesis and stability of organometallic complexes bearing ligand tethers. With ligands in hand, the synthesis of palladium complexes will be undertaken. Eventual catalytic conditions will require the presence of both acid and water. The stability of our prospective catalysts under these conditions will be evaluated. (3) Catalyst testing and substrate scope. Complexes will be evaluated for their ability to facilitate C-H functionalization based on reaction rate and regioselectivity. Functional group tolerance will also be explored. In the long term we will work to extend our ?tether? methodology to additional pharmaceutically relevant substrate classes.